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Distinctive role of DICER1 mutations in distant metastatic thyroid cancer
Cong Shi1,2, Zhuanzhuan Mu1,2, Wenting Guo3
1Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Objective:
This study investigated the clinical significance of DICER1 mutations in patients with distant metastatic follicular cell-derived thyroid cancer (FDTC).
Methods:
This study included 310 Chinese patients with distant metastatic FDTC. We analyzed the interactions between DICER1 mutations and other gene alterations and compared the clinicopathological characteristics of patients with pathogenic (P) or likely pathogenic (LP) DICER1 mutations (n=9), other gene alterations (n=253), and no gene alterations (n=37). To compare FDTCs with different drivers, isolated BRAFV600E, RAS mutations, and RET fusions were compared with isolated DICER1 mutations.
Results:
The prevalence of DICER1 mutations was 6.5% (20/310) in the patient cohort. Among patients with DICER1 mutations, 45% (9/20) harbored P or LP DICER1 variants and 55% (11/20) harbored DICER1 variants of uncertain significance (VUS). The coexistence of DICER1 mutations and other gene alterations was detected in 65% (13/20) of patients. Compared with VUS, P or LP DICER1 variants were almost mutually exclusive with early driver alterations (such as BRAFV600E) (11.1% vs. 81.8%, P=0.002) and more coexisted with late-hit events, particularly TP53 mutations (44.4% vs. 27.3%, P=0.642). Clinically, compared with the no alteration and other alteration groups, the DICER1 mutation group exhibited larger primary tumors, higher poorly differentiated thyroid cancer proportion, more extrathyroidal extension, more extrapulmonary metastases, and higher radioactive iodine-refractory proportion (all P<0.05). Cases with isolated DICER1 mutations differed from those with isolated BRAFV600E and RET fusions in terms of tumor size, poorly differentiated thyroid cancer proportion, and metastatic sites, but were similar to cases with isolated RAS mutations in the high proportion of follicular thyroid cancer, N0, and extrapulmonary metastases.
Conclusions:
Mutation of DICER1 gene is a non-negligible molecular event and it may represent an aggressive subset of FDTCs. DICER1 has RAS-like clinical characteristics and DICER1-mutant tumors exhibit more aggressive clinical behaviors compared with those with BRAFV600E and RET fusions.
Insights
DICER1 gene mutations are found in 6.5% of distant metastatic follicular cell-derived thyroid cancer (FDTC) patients. These mutations indicate a more aggressive cancer subset with RAS-like characteristics.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Follicular cell-derived thyroid cancer (FDTC) with distant metastases presents significant clinical challenges.
- Understanding the molecular drivers of aggressive FDTC is crucial for targeted therapies.
Purpose of the Study:
- To investigate the clinical significance of DICER1 gene mutations in patients with distant metastatic FDTC.
- To analyze the interactions between DICER1 mutations and other genetic alterations.
- To compare clinicopathological characteristics based on DICER1 mutation status.
Main Methods:
- Analysis of 310 Chinese patients with distant metastatic FDTC.
- Genomic analysis to identify DICER1 mutations and co-occurring alterations.
- Comparison of clinicopathological features between groups with pathogenic/likely pathogenic DICER1 mutations, other gene alterations, and no alterations.
- Comparative analysis of isolated DICER1 mutations against BRAFV600E, RAS mutations, and RET fusions.
Main Results:
- DICER1 mutations were present in 6.5% of the cohort.
- Pathogenic/likely pathogenic DICER1 variants were mutually exclusive with early drivers like BRAFV600E but coexisted with TP53 mutations.
- DICER1-mutated FDTC exhibited larger tumors, higher poorly differentiated cancer proportion, increased extrathyroidal extension, more extrapulmonary metastases, and higher radioactive iodine-refractory rates.
- DICER1 mutations showed RAS-like clinical characteristics, differing from BRAFV600E and RET fusions but similar to RAS mutations in specific aspects.
Conclusions:
- DICER1 gene mutation is a significant molecular event in FDTC.
- DICER1 mutations identify an aggressive subset of FDTC.
- DICER1-mutant tumors display more aggressive clinical behaviors than those with BRAFV600E or RET fusions.
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